Multi-omics Studies of Childhood Complex Traits

National Human Genome Research Institute

Investigators

Linked publications, trials & patents

Abstract

Genomic characterization of populations The global burden of severe childhood malnutrition and disorders of hemoglobin falls disproportionately on populations of African ancestry. As part of the H3Africa Consortium (Rotimi et al, 2014), we previously demonstrated that African ancestry populations harbor the most- and most complex- genetic sequence variation among continental populations (Choudhury et al, 2020), despite being underrepresented in public databases of genetic variation. We continue to collaborate on efforts to expand the landscape of known African genetic variation as a means of facilitating robust genetic mapping in these populations and improved precision health globally. During this reporting period: - Whole-genome sequencing of ~1200 native Africans was completed as part of the Assessing Genome Diversity in Africa (AGenDA) project of H3Africa. We have developed detailed data analysis plans to be completed over the next 12 months. We also contributed to a collaborative manuscript outlining the premise and first (recruitment) phase of the project; this is currently undergoing a second round of review at Nature. These external efforts were complemented by the development of an in-house database to view and report allele frequencies of variants uncovered in any of our sequencing cohorts. - We completed and submitted a manuscript describing the use of newer sequencing technology to fully expound the genetic variation across the region encoding the beta-globin protein, which includes the gene causing sickle cell disease and related disorders of hemoglobin. We identified and validated novel variation by aligning data to the telomere-to-telomere (T2T) human genome reference and found that compared to the previous genome build, the T2T reference revealed unrecognized genetic variants and reduced false positive variant calls. This manuscript is in revision. - We completed and submitted our manuscript characterizing epigenetic correlations across the genome. We found that at the population level, the number of methyl groups added to specific DNA sequences (DNA methylation) is strongly correlated across ~1,000 base pairs. Correlated units vary in size by tissue and tend to bring together genes with shared gene regulation. This observation should make it easier to define and understand differences in DNA methylation that can contribute to disease pathogenesis. The manuscript describing our findings received a favorable review and is being revised for resubmission. - We completed a series of studies outlining inter-geographical variation among genetic loci associated with HIV disease progression in African children (collaboration with NIEHS). These data underscore the complexity and uniqueness of genetic mapping in African ancestry populations. - We competed for and received an intramural NIH funding grant to support the development of cloud-computing to facilitate integration of the datasets generated as part of this project. Childhood Severe Acute Malnutrition (SAM) Our previous studies identified DNA hypomethylation in children with the more-deadly edematous form of SAM (known as ESAM) relative to the non-edematous form (NESAM) (Schulze et al, 2019). We also reported differences in one-carbon metabolism (OCM) between children with ESAM and those with NESAM (May, et al, 2022) and championed a call for more research into the cause of ESAM (May, et. al, 2023). In this reporting period, we: - Revised and resubmitted our manuscript demonstrating a shared east-African genetic background associated with increased risk of ESAM - Extended our cellular model of starvation-induced fatty liver to include a longitudinal study of molecular changes following starvation of immortalized liver cells. A manuscript outlining our findings is in development. - Supported recruitment of 1,620 of a projected ~10,000 clinically-phenotyped ESAM cases and NESAM controls across the 7 countries of the Kwashiorkor Study Network (KwashNet), which we established in the previous reporting period. - Launched and tested a real-time electronic data collection tool (IQapture) specifically designed for use in clinical research studies being conducted in low-to-middle income countries. IQapture was created in collaboration with a local US-based industry leader in the LMIC clinical space. Risk of transfusion reactions in Sickle Cell Disease We previously published a genome-wide association of alloimmunization risk in sickle cell disease (SCD) (Williams et al, 2018) in which we identified a genome-wide significant association between variants within an intergenic locus on chromosome 5q33 and the increased propensity of some individuals with SCD to develop antibodies to transfused red blood cells (alloantibodies). We continued expanding our knowledge of tissue-specific gene transcription and gene regulation at the 5q33 locus and have established new clinical collaborations within and external to NIH to facilitate a clinical cohort of variant positive and variant negative individuals with SCD. These studies aim to molecularly characterize an important but poorly understood clinical outcome that could transform transfusion medicine. In this reporting period we: - Obtained IRB approval for our clinical protocol to recontact and recruit SCD individuals for molecular and clinical phenotyping. We also recruited the first two protocol patients to the NIH Clinical Center - Finalized a protocol to use immune stimulation and single cell multi-omics technologies to evaluate the expression and regulation of genes at the 5q33 locus in patient samples. - Compared gene expression and gene regulation at 5q33 in peripheral blood with that in human spleen, the primary tissue of alloimmunization (facilitated through collaboration with NCI investigators). - Worked alongside the All of Us Project core to identify association between our 5q33 alloimmunization SNP and the development of ‘anemia of chronic disease’, exemplifying the relevance of our study to other common complex disorders.